Mechanisms of Transcriptional Regulation in Eukaryotes

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): The long-term objective of this project is to understand the factors and mechanisms that are involved in the regulation of transcription by RNA polymerase II. This work focuses in particular upon the core promoter. The core promoter is at a unique and strategic position in the transcription process, as it is the gateway through which all transcripts must be synthesized. The best-known core promoter element is the TATA box, but the TATA box appears to be present only in about one-third of human genes. Therefore, this project has focused on the study of TATA-less core promoters and the functions of the DPE and MTE core promoter elements. Notably, the mechanism of DPE-directed transcription is distinct from that of TATA- directed transcription. Moreover, some transcriptional enhancers function specifically with either DPE- or TATA-dependent core promoters. Thus, the core promoter functions not only in the specification of the transcription start site, but also in the communication between enhancers and promoters. The first specific aim explores the sequences that mediate MTE and DPE function, the interaction of TFIID with the MTE, the role of TBP in DPE- and MTE-directed transcription, the discovery of new core promoter motifs, and pharmaceutical applications of the core promoter. The second specific aim focuses on the study of novel basal transcription factors that are involved in transcription from DPE- and MTE-dependent core promoters. The third specific aim investigates transcriptional enhancers from the unique perspective of the core promoter. Transcriptional enhancers were discovered over 20 years ago, but the molecular mechanisms by which they function remain largely a mystery. The proposed experiments address this important yet unsolved problem by analysis of the specificity of enhancers for DPE or TATA core promoter elements. These studies should lead to a better understanding of gene regulation, and should therefore provide new insights into the molecular basis and potential treatment of human diseases, such as many forms of cancer, that involve abnormalities in the control of the expression of genes.